Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.
Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity.
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DOI：
10.1016/j.ccell.2017.11.012
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发表时间：
2018-01-08
期刊：
影响因子：
50.3
通讯作者：
Shih AH
中科院分区：
文献类型：
--
作者：
Kunimoto H;Meydan C;Nazir A;Whitfield J;Shank K;Rapaport F;Maher R;Pronier E;Meyer SC;Garrett-Bakelman FE;Tallman M;Melnick A;Levine RL;Shih AH
表观遗传修饰物和信号因子的突变经常在髓系恶性肿瘤中共同出现，包括TET2和NRAS突变。TET2缺失和NrasG12D同时在造血细胞中表达，可诱导髓系转化，可连续移植的完全穿透性、致死性慢性粒单核细胞白血病(CMML)。TET2缺失和NRAS突变协同导致丝裂原活化蛋白激酶(MAPK)激活的负调控因子减少，包括SPRY2，从而通过表观遗传沉默导致MAPK信号的协同激活。在小鼠模型和患者样本中，TET2/NRAS双突变白血病对MAPK激酶(MEK)抑制均表现出优先敏感性。这些数据为表观遗传和信号突变如何在髓系转化中合作提供了洞察力，并为患有这些高危遗传损害的CMML患者提供了基于机制的治疗的理论基础。Kunimoto等人。结果表明，TET2缺失和NrasG12D在造血细胞中的同时表达通过减少MAPK激活的负调控因素而诱导完全穿透性、致死性慢性粒单核细胞白血病。小鼠和人TET2/NRAS双突变白血病对MEK抑制表现出优先敏感性。
Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML) which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing. Tet2/Nras double-mutant leukemia showed preferential sensitivity to MAPK kinase (MEK) inhibition in both mouse model and patient samples. These data provide insights into how epigenetic and signaling mutations cooperate in myeloid transformation and provide a rationale for mechanism based therapy in CMML patients with these high-risk genetic lesions. Kunimoto et al. show that concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induces fully penetrant, lethal chronic myelomonocytic leukemia by decreasing negative regulators of MAPK activation. Mouse and human TET2/NRAS double-mutant leukemia show preferential sensitivity to MEK inhibition.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
64.5
作者：
Burgess MR;Hwang E;Mroue R;Bielski CM;Wandler AM;Huang BJ;Firestone AJ;Young A;Lacap JA;Crocker L;Asthana S;Davis EM;Xu J;Akagi K;Le Beau MM;Li Q;Haley B;Stokoe D;Sampath D;Taylor BS;Evangelista M;Shannon K
通讯作者：
Shannon K
影响因子：
1.2
作者：
Khanna, Vishesh;Pierce, Scott T.;Druker, Brian J.
通讯作者：
Druker, Brian J.
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL